Hepatitis C virus (HCV) infection is a major health problem. HCV infection leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals.
Several virally-encoded enzymes are putative targets for therapeutic intervention, including a metalloprotease (NS2-3), a serine protease (NS3), a helicase (NS3), and an RNA-dependent RNA polymerase (NS5B). The NS3 protease is located in the N-terminal domain of the NS3 protein. NS4A provides a cofactor for NS3 activity.
Examples of publications describing macrolactam compounds able to inhibit HCV protease activity include: Harper et al., WO 2010/011566; Liverton et al., WO 2009/134624; McCauley et al., WO 2009/108507; Liverton et al., WO 2009/010804; Liverton et al., WO 2008/057209; Liverton et al., WO 2008/051477; Liverton et al., WO 2008/051514; Liverton et al., WO 2008/057208; Crescenzi et al., WO 2007/148135; Di Francesco et al., WO 2007/131966; Holloway et al., WO 2007/015855; Holloway et al., WO 2007/015787; Holloway et al., WO 2007/016441; Holloway et al., WO 2006/119061; Liverton et al., J. Am. Chem. Soc. 130:4607-4609, 2008; and Liverton et al., Antimicrobial Agents and Chemotherapy 54:305-311, 2010.